Role of Aspartate in Immune Response and Mortality in a Polymicrobial Sepsis Model: Insights from Metabolomics and Transcriptomics

TL;DR

This study shows that low aspartate levels in immune cells during sepsis are linked to immune failure and that supplementing aspartate improves survival and immune function in septic rats and humans.

Contribution

The study identifies intracellular aspartate as a novel biomarker and therapeutic target for immune suppression in sepsis.

Findings

Intracellular aspartate levels are reduced in immune cells during sepsis and correlate with immune paralysis.

Supplementing aspartate with LOLA improves survival, bacterial clearance, and kidney function in septic rats.

Sepsis patients have lower intracellular aspartate levels in PBMCs compared to healthy individuals.

Abstract

Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection. In addition to early hyperinflammation, many patients develop profound immune suppression, and multiple targeted immunotherapies have failed to improve outcomes, highlighting the need for actionable biomarkers and new therapeutic strategies. Here, we integrated metabolomic and transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and splenocytes in rat models of polymicrobial sepsis to identify metabolites associated with immune dysfunction. Candidate findings were validated using in vivo supplementation studies and in vitro functional assays, and clinical relevance was assessed in PBMCs from patients with sepsis and healthy volunteers. Across omics datasets, intracellular aspartate (ASP) was consistently reduced in immune cells during sepsis and was associated with features of immune paralysis. Supplementation with L-ornithine L-aspartate (LOLA), an ASP source, improved survival in septic rats, enhanced bacterial clearance, and mitigated acute kidney injury. In vitro, pharmacologic or genetic disruption of ASP production impaired phagocytosis and cytokine responses, which were partially rescued by ASP supplementation. Consistently, patients with sepsis exhibited lower intracellular ASP levels in PBMCs than healthy volunteers. Together, these results support a critical role for ASP in maintaining immune competence during sepsis and suggest that intracellular ASP may serve as a biomarker of immune suppression and a potential therapeutic target.

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